JP6714225B2 - Medicine for the prevention or treatment of hepatocellular carcinoma - Google Patents
Medicine for the prevention or treatment of hepatocellular carcinoma Download PDFInfo
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- JP6714225B2 JP6714225B2 JP2017515497A JP2017515497A JP6714225B2 JP 6714225 B2 JP6714225 B2 JP 6714225B2 JP 2017515497 A JP2017515497 A JP 2017515497A JP 2017515497 A JP2017515497 A JP 2017515497A JP 6714225 B2 JP6714225 B2 JP 6714225B2
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- hepatocellular carcinoma
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、ピラゾロピリミジン誘導体を有効成分とする、肝細胞癌の予防又は治療のための医薬に関するものである。 The present invention relates to a medicament for preventing or treating hepatocellular carcinoma, which comprises a pyrazolopyrimidine derivative as an active ingredient.
肝細胞癌とは、肝臓に発生する悪性腫瘍の一つで、肝臓の細胞が癌化する原発性の肝癌である。肝細胞癌の発生原因としては、C型肝炎、B型肝炎、NASH、アルコール性肝炎等が挙げられる。 Hepatocellular carcinoma is one of malignant tumors occurring in the liver and is a primary liver cancer in which cells of the liver become cancerous. The causes of hepatocellular carcinoma include hepatitis C, hepatitis B, NASH, alcoholic hepatitis and the like.
CD26は免疫調節作用等の多様な機能を有した膜タンパクであるが、細胞外ペプチダーゼとしても作用し、ジペプチジルペプチダーゼ4(DPP4)とも言われている。CD26は様々な癌細胞における発現が報告されている。近年、CD26蛋白の過剰発現は、様々な悪性腫瘍の増殖・浸潤に影響を及ぼすことが指摘されている（非特許文献１、２、３）。しかし、肝細胞癌(HCC)の増殖に対するCD26の影響については文献的報告がされていない。 Although CD26 is a membrane protein having various functions such as immunomodulatory action, it also acts as an extracellular peptidase and is also called dipeptidyl peptidase 4 (DPP4). Expression of CD26 in various cancer cells has been reported. In recent years, it has been pointed out that overexpression of CD26 protein affects proliferation and invasion of various malignant tumors (Non-patent Documents 1, 2, 3). However, there is no literature report on the effect of CD26 on the proliferation of hepatocellular carcinoma (HCC).
現在、肝細胞癌の治療としては、例えば、外科的肝切除、経皮的局所療法（経皮的エタノール注入療法や、経皮的ラジオ波焼灼療法等）、栄養動脈を塞栓し腫瘍を阻血壊死に陥らせる肝動脈塞栓療法、肝動脈に抗癌剤を注入する肝動注化学療法、栄養動脈を塞栓するとともに抗癌剤を投与する肝動脈化学塞栓療法、経口または経静脈的に抗癌剤を投与する全身化学療法などが行われている。抗癌剤としては、アルキル化剤（シクロホスファミド）、代謝拮抗剤（フルオロウラシル、テガフール・ウラシル配合剤）、抗生物質（マイトマイシンＣ、ドキソルビシン、エピルビシン、ミトキサントロン）、白金製剤（シスプラチン）等が、単独又は併用で用いられている。しかしながら、これらの抗癌剤が肝細胞癌の治療薬として必ずしも満足されているとは言えず、新たな肝細胞癌治療薬が望まれている。 Currently, the treatment of hepatocellular carcinoma includes, for example, surgical liver resection, percutaneous local therapy (percutaneous ethanol injection therapy, percutaneous radiofrequency ablation therapy, etc.), embolization of the feeding artery and ischemic necrosis of the tumor. Arterial embolization therapy that injects anticancer drug into hepatic artery, hepatic arterial chemoembolization therapy that embolizes feeding artery and administers anticancer drug, systemic chemotherapy that administers anticancer drug orally or intravenously And so on. Examples of anticancer agents include alkylating agents (cyclophosphamide), antimetabolites (fluorouracil, tegafur/uracil combination agents), antibiotics (mitomycin C, doxorubicin, epirubicin, mitoxantrone), platinum preparations (cisplatin), etc. Used alone or in combination. However, these anticancer agents are not always satisfactory as therapeutic agents for hepatocellular carcinoma, and new therapeutic agents for hepatocellular carcinoma are desired.
DPP-IV阻害作用を有する化合物の癌に対する予防又は治療効果については、例えば、DPP-IV阻害剤である、ペプチド化合物、ペプチジルケトン、及びアミノケトン誘導体等が腫瘍転移増殖の治療に有用であることが報告されている（特許文献１）。一方、縮合イミダゾール誘導体（特許文献２）、１，３−ジヒドロ−イミダゾール縮合環化合物（特許文献３）、ピロリジン及びチアゾリジンDPP-IV阻害化合物（特許文献４）については、癌に対する有効性について報告されているが、データに基づく具体的な開示は一切ない。 Regarding the preventive or therapeutic effects on cancer of compounds having a DPP-IV inhibitory action, for example, DPP-IV inhibitors, peptide compounds, peptidyl ketone, and aminoketone derivatives may be useful in the treatment of tumor metastasis growth. It has been reported (Patent Document 1). On the other hand, regarding the condensed imidazole derivative (Patent Document 2), 1,3-dihydro-imidazole condensed ring compound (Patent Document 3), pyrrolidine and thiazolidine DPP-IV inhibitor compound (Patent Document 4), the efficacy against cancer is reported. However, there is no specific disclosure based on the data.
ところで、WO2004/067509（特許文献５）に記載された本発明にかかる化合物であるＮ−［２−（｛２−［（２Ｓ）−２−シアノピロリジン−１−イル］−２−オキソエチル｝アミノ）−２−メチルプロピル]−２−メチルピラゾロ［１，５−ａ］ピリミジン−６−カルボキサミド（一般名：アナグリプチン）及びその周辺の化合物は、DPP-IV阻害作用を有する化合物として知られているが、このものがどのような癌に対しどのような影響を及ぼすかについてはまったく知られておらず、更に肝細胞癌に対する有効性についても知られていない。 By the way, N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino which is the compound according to the present invention described in WO2004/067509 (Patent Document 5). )-2-Methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide (generic name: anagliptin) and its peripheral compounds are known as compounds having a DPP-IV inhibitory action. However, it is not known at all what kind of effect this cancer has on what kind of cancer, nor is it known about the efficacy against hepatocellular carcinoma.
本発明が解決しようとする課題は、肝細胞癌の予防又は治療に用いる新たな医薬を提供することにある。 The problem to be solved by the present invention is to provide a new drug used for the prevention or treatment of hepatocellular carcinoma.
本発明の発明者らは、上記の課題を解決すべく研究を行った結果、DPPIV阻害薬である下記ピラゾロピリミジン誘導体が、肝細胞癌の予防又は治療に有用であることを見出し、本発明を完成するに至った。 The inventors of the present invention, as a result of conducting research to solve the above problems, found that the following pyrazolopyrimidine derivatives, which are DPPIV inhibitors, are useful in the prevention or treatment of hepatocellular carcinoma, Was completed.
即ち、本発明は、次の通りである。
＜１＞ 下記一般式（Ｉ）で表される化合物又はその塩を有効成分として含有する、肝細胞癌の予防又は治療に用いる医薬。
＜２＞ 前記有効成分が、N-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミド又はその塩である、＜１＞に記載の医薬。
＜３＞ 前記有効成分がN-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミド（アナグリプチン）である、＜１＞に記載の医薬。That is, the present invention is as follows.
<1> A medicament for use in the prevention or treatment of hepatocellular carcinoma, which comprises a compound represented by the following general formula (I) or a salt thereof as an active ingredient.
<2> The active ingredient is N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1 The medicament according to <1>, which is a 5,5-a]pyrimidine-6-carboxamide or a salt thereof.
<3> The active ingredient is N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1, 5-a]pyrimidine-6-carboxamide (anagliptin), The medicament according to <1>.
本発明の医薬は、肝細胞癌の予防又は治療に用いることができる。 The medicament of the present invention can be used for prevention or treatment of hepatocellular carcinoma.
以下に、本発明を更に詳細に説明する。本発明の肝細胞癌の予防又は治療に用いる医薬は、以下の一般式（Ｉ）で表わされる化合物又はその塩を有効成分として含有する。中でも、N-[2-({2-[(2S)-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミド（一般名：アナグリプチン（anagliptin））が好ましい。これらの化合物は、特許文献５（WO2004/067509）記載の化合物であり、その実施例１の化合物の製造法又は実施例２の化合物の製造法等により製造することができる。 Hereinafter, the present invention will be described in more detail. The medicament of the present invention used for preventing or treating hepatocellular carcinoma contains a compound represented by the following general formula (I) or a salt thereof as an active ingredient. Among them, N-[2-({2-[(2S)-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6 -Carboxamide (generic name: anagliptin) is preferred. These compounds are compounds described in Patent Document 5 (WO2004/067509), and can be produced by the method for producing the compound of Example 1 or the method for producing the compound of Example 2 and the like.
塩を形成する場合、該塩としては、薬理学的に許容される塩が好ましく、例えば無機酸との塩、有機酸との塩、塩基性又は酸性アミノ酸との塩等が挙げられる。無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、安息香酸、トルエンスルホン酸塩等との塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、アルギニン等との塩が挙げられる。酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸等との塩が挙げられる。 When forming a salt, the salt is preferably a pharmacologically acceptable salt, and examples thereof include a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, toluenesulfonic acid salt and the like. And salt. Preferable examples of salts with basic amino acids include salts with arginine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
本発明の医薬は肝細胞癌に対して有効である。すなわち、本発明の医薬は、肝細胞癌の予防又は治療のための医薬としての用途を有している。肝細胞癌とは、肝臓に発生する悪性腫瘍の一つで、肝臓の細胞が癌化する原発性の肝癌である。肝細胞癌の原因としては、B型肝炎、C型肝炎、NASH、アルコール性肝炎等が挙げられるが、ほとんどはB型あるいはC型肝炎を背景に発生する。 The medicament of the present invention is effective against hepatocellular carcinoma. That is, the medicament of the present invention has use as a medicament for the prevention or treatment of hepatocellular carcinoma. Hepatocellular carcinoma is one of malignant tumors occurring in the liver and is a primary liver cancer in which cells of the liver become cancerous. The causes of hepatocellular carcinoma include hepatitis B, hepatitis C, NASH, alcoholic hepatitis, etc., but most of them occur against the background of hepatitis B or C.
一般式（Ｉ）で表される化合物又はその塩の投与量は、症状、年齢、性別、投与法、剤形等により異なるが、通常の場合には、成人に対し本発明化合物として１日当たり0.1〜1000mgの範囲内、好ましくは1〜400mgを１日当たり１回又は数回に分けて連日投与するのが好ましい。 The dose of the compound represented by the general formula (I) or a salt thereof varies depending on the symptoms, age, sex, administration method, dosage form, etc. It is preferable to administer daily doses in the range of up to 1000 mg, preferably 1 to 400 mg once or several times a day.
本発明の医薬は、通常の製剤技術により、例えば、錠剤、カプセル剤、散剤、顆粒剤、液剤、若しくはシロップ剤として経口的に、又は注射剤若しくは点耳剤等として非経口的に投与することができる。 The drug of the present invention can be administered orally as a tablet, capsule, powder, granule, liquid or syrup, or parenterally as an injection or ear drop, etc., by a conventional formulation technique. You can
製剤化については、固形剤の場合には、製剤化に際して薬理学的に認容し得る賦形剤、例えば、澱粉、乳糖、精製白糖、グルコース、結晶セルロース、カルボキシセルロース、カルボキシメチルセルロース、カルボキシエチルセルロース、燐酸カルシウム、ステアリン酸マグネシウム、及び／又はアラビアゴム等を用いることができ、必要であれば、滑沢剤、結合剤、崩壊剤、被覆剤、及び／又は着色剤等を配合することができる。また、液剤の場合には、安定剤、溶解助剤、懸濁化剤、乳化剤、緩衝剤、及び／又は保存剤等を用いることができる。 For formulation, in the case of a solid formulation, a pharmacologically acceptable excipient during formulation, for example, starch, lactose, purified sucrose, glucose, crystalline cellulose, carboxycellulose, carboxymethylcellulose, carboxyethylcellulose, phosphoric acid Calcium, magnesium stearate, and/or gum arabic can be used, and if necessary, a lubricant, a binder, a disintegrating agent, a coating agent, and/or a coloring agent can be added. Further, in the case of liquid preparations, stabilizers, solubilizers, suspending agents, emulsifiers, buffers, and/or preservatives can be used.
本発明の医薬には、その有効成分たる一般式（Ｉ）で表わされる化合物又はその塩に加えて、さらに、肝細胞癌の既存薬であるアルキル化剤（シクロホスファミド）、代謝拮抗剤（フルオロウラシル、テガフール・ウラシル配合剤）、抗生物質（マイトマイシンＣ、ドキソルビシン、エピルビシン、ミトキサントロン）、及び白金製剤（シスプラチン）からなる群より選ばれる１種以上を組み合わせることができる。これら既存薬は、前記一般式（Ｉ）で表わされる化合物又はその塩と同時に投与してもよく、また、別のタイミングで投与してもよい。 The drug of the present invention includes, in addition to the compound represented by the general formula (I) or its salt as an active ingredient thereof, an alkylating agent (cyclophosphamide) which is an existing drug for hepatocellular carcinoma, and an antimetabolite. (Fluorouracil, tegafur/uracil compounding agent), antibiotics (mitomycin C, doxorubicin, epirubicin, mitoxantrone), and one or more selected from the group consisting of platinum agents (cisplatin) can be combined. These existing drugs may be administered at the same time as the compound represented by the general formula (I) or a salt thereof, or may be administered at a different timing.
既存薬と組み合わせた本発明の医薬の形態としては、一般式（Ｉ）で表わされる化合物又はその塩と既存薬の両成分を共に含有する単一製剤（いわゆる配合剤）の形態、既存薬と一般式（Ｉ）で表わされる化合物又はその塩を別々に投与するための形態、及び、既存薬と一般式（Ｉ）で表わされる化合物又はその塩を単一包装中に含む組み合わせキット製剤の形態が挙げられる。 Examples of the pharmaceutical form of the present invention in combination with an existing drug include a single preparation (so-called combination drug) containing both the compound represented by formula (I) or a salt thereof and both components of the existing drug, and the existing drug. Form for separately administering the compound represented by the general formula (I) or a salt thereof, and form of a combination kit preparation containing an existing drug and the compound represented by the general formula (I) or a salt in a single package Are listed.
肝細胞癌の既存薬の投与量は、薬物によって異なり、それぞれの薬剤で規定されている通常の用法および用量に従って投与するのが好ましい。 The dose of the existing drug for hepatocellular carcinoma varies depending on the drug, and it is preferable to administer the drug according to the usual usage and dose prescribed for each drug.
次に、実施例を挙げて本発明を更に説明するが、本発明はこれらに限定されるものではない。
試験例１：nude mouse xenograftを用いた抗腫瘍効果の検討
（試験方法）
６週齢のnude mouse（BALBc-nu/nu，雄性）に肝細胞癌株Huh-7を2×106個皮下移植した。移植した細胞の生着・増殖を確認するために、腫瘍サイズをノギスで計測し、腫瘍の体積が100〜150mm2となった時点で、以下の3群（1群5匹）に群分けした。
（１）対照群：MF固型飼料を21日間与えた。
（２）アナグリプチン低用量群：アナグリプチンをMF飼料に混合した固形飼料を100mg/kg/日となるように21日間与えた。
（３）アナグリプチン高用量群：アナグリプチンをMF飼料に混合した固形飼料を300mg/kg/日となるように21日間与えた。
投与開始から3日毎に腫瘍体積を計測し、腫瘍体積の経時的推移を評価した。また、投与開始21日後にマウスを安楽死させて腫瘍を採取し、腫瘍の肉眼的観察等を行った。Next, the present invention will be further described with reference to examples, but the present invention is not limited thereto.
Test Example 1: Examination of antitumor effect using nude mouse xenograft (test method)
2×10 6 hepatocellular carcinoma strains Huh-7 were subcutaneously transplanted into 6-week-old nude mice (BALBc-nu/nu, male). In order to confirm the engraftment/proliferation of the transplanted cells, the tumor size was measured with a caliper, and when the tumor volume reached 100 to 150 mm 2 , the tumor was grouped into the following 3 groups (5 animals per group). ..
(1) Control group: MF solid feed was given for 21 days.
(2) Anagliptin low-dose group: A solid feed prepared by mixing anagliptin with MF feed was given for 21 days at 100 mg/kg/day.
(3) High-dose anagliptin group: A solid feed prepared by mixing anagliptin with MF feed was given for 21 days at 300 mg/kg/day.
The tumor volume was measured every 3 days from the start of administration, and the time course of the tumor volume was evaluated. In addition, 21 days after the start of administration, the mouse was euthanized, the tumor was collected, and the tumor was visually observed.
（結果）
投与開始21日後の各群の各個体の腫瘍の写真を図１に、各群の腫瘍体積（平均値±標準偏差）の経時的推移を図２に示した。このように、アナグリプチンの投与群では、無投与群と比較して、移植された肝細胞癌の腫瘍サイズを抑制する効果が見られ、特に高用量群では、統計的に有意な効果を示した。従って、アナグリプチンは、肝細胞癌の予防又は治療剤として有用であることがわかった。(result)
A photograph of the tumor of each individual in each
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